Schizophrenia is a common, severe mental disorder, and a leading public health problem worldwide. Growing evidence supports a role for neurodevelopment in the pathophysiology of schizophrenia. Multiple genes, interacting with each other and with environmental factors, are also believed to be involved. Recently, several independent lines of evidence have implicated the synapsin III gene in biochemical pathways that may increase susceptibility to schizophrenia. The human synapsin III gene is located on chromosome 22q12.3, a previously described schizophrenia susceptibility locus. We have identified a rare synapsin III polymorphism, which inactivates a site that is highly phosphorylated in response to neurotrophins. Our studies have demonstrated that synapsin III is predominantly expressed in early development, and plays a role in axon outgrowth and neurogenesis. Synapsin III levels have also been reported to be profoundly decreased in postmortem hippocampi of individuals affected with schizophrenia. Finally, our preliminary data indicates that mice lacking the synapsin III gene demonstrate abnormalities in sensorimotor gating, which were reversed by treatment with an antipsychotic agent. Our long term objective is to understand the neurobiology of neuropsychiatric diseases. The proposed research seeks to determine the role of synapsin III in neurodevelopmental pathways underlying schizophrenia by pursuing three specific aims. In Aim 1, the functional consequences of a rare polymorphism in the human synapsin III gene will be determined by using affinity chromatography and mass spectrometry to identify proteins interacting with the polymorphic site, determining the functional outcomes of these protein interactions, and establishing the effects of the polymorphism on development and neurotransmission in neuronal cell culture. In Aim 2, the role of synapsin III in specific stages of neurogenesis will be determined by quantifying proliferation, differentiation, and apoptosis of neural stem cells in the hippocampal dentate gyrus and olfactory bulb of synapsin III knockout and control mice during early and late development. In Aim 3, we will determine the behavioral phenotype of synapsin III knockout mice. It is our expectation that these studies will define new biochemical pathways that are involved in susceptibility to schizophrenia, which may lead to the identification of novel targets for the prevention and treatment of this disease.